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10N,O-Macrocycles ^O-Макроциклы
Макрогэтэроцмклы
http://macroheterocycles.isuct.ru
Paper Статья
DOI: 10.6060/mhc161071a
Synthesis of Macrocycles Containing Endocyclic Chiral BINAM Moieties
Olga K. Grigorova, Alexei D. Averin,@ Olga A. Maloshitskaya, and Irina P. Beletskaya
Lomonosov Moscow State University, Department of Chemistry, 119991 Moscow, Russia @Corresponding author E-mail: alexaveron@yandex.ru
A series of nitrogen- and oxygen-containing macrocycles with endocyclic chiral BINAM moieties were synthesized using Pd(0)-catalyzed amination with a number of oxadiamines. Two alternative ways to such compounds were compared - from 1,1'-binaphthalene-2,2'-diamine (BINAM) and N,N'-bis(3-bromophenyl) substituted oxadiamine and from N,N'-bis(bromophenyl) substituted 1,1'-binaphthalene-2,2'-diamine and free oxadiamine. Macrocycles containing benzyl and 2,7-disubstituted naphthalene fragments were also successfully synthesized via the second approach, the dependence of their yields on the nature of starting compounds was demonstrated.
Keywords: Macrocycles, chirality, Pd catalysis, amination, polyamines.
Синтез макроциклов, содержащих эндоциклические хиральные BINAM фрагменты
O. ^ Григорова, A. Д. Аверин,@ O. A. Малошицкая, И. П. Белецкая
Московский государственный университет им. М.В. Ломоносова, 119991 Москва, Россия @Е-таИ: alexaveron@yandex.ru
Синтезирован ряд азот- и кислородсодержащих макроциклов с эндоциклическим хиральным фрагментом БИНАМ посредством Pd(0)-каталuзuруемого аминирования с использованием ряда оксадиаминов. Произведено сравнение двух альтернативных путей получения таких соединений - из 1,1'-бинафталин-2,2'-диамина (БИНАМ) и И,И'-ди(3-бромфенил) замещенного оксадиамина и из И,И'-ди(3-бромфенил) замещенного 1,1'-бинафталин-2,2'-диамина и свободного оксадиамина. Макроциклы, содержащие бензильный и 2,7-дизамещенный нафтильный фрагменты также успешно синтезированы с использованием второго метода, показана зависимость их выходов от природы исходных соединений.
Ключевые слова: Mакроциклы, Pd катализ, хиральность, аминирование, полиамины.
Introduction
Macrocyclic compounds comprising endocyclic chiral moieties attract attention of researchers as biologically active compounds, perspective chemosensors for small chiral molecules, and ligands which can be used in enantioselective metal-catalyzed transformations. Such compounds occur in nature, among them the prominent place is occupied by macrolides, cyclic oligopeptides and cyclic
oligosaccharides. These compounds contain multiple carbon chiral centers, and the majority of optically active synthetic macrocycles possess the same type of chirality. Enough rare are synthetic macrocyclic compounds with another type of chirality, i.e. planar-chiral macrocycles,[1-3] and our previous works contributed to this field.[4,5] Also we elaborated a new type ofmacrocycles with endocyclic chiral cholane fragments. [6-9] Macrocyclic compounds containing fragments with C2 chirality are known for quite a long time, and the majority
of them possess 2,2'-binaphthol (BINOL) moiety. Some of them were reported before 1991 when a comprehensive review on all types of known macrocycles emerged.[10] As this chiral moiety possesses fluorescent properties, BINOL-based chemosensors were found to be useful for detecting optically active amino alcohols, diamines, amino acids, a-hydroxyacids.[11,12] Reported are several macrocycles containing BINOL fragment which contain also additional chiral 1,2-diamine moieties.[13,14] These compounds were synthesized via non-catalytic approaches, and in the course of our studies of the application of the catalytic amination to the synthesis of various nitrogen-containing macrocycles we decided to elaborate a general route to the macrocyclic species containing a parent chiral 1,1'-binaphthalene-2,2'-diamine (BINAM) structural units. BINAM itself possesses interesting spectral properties, and in the combination with other aromatic and heteroaromatic groups the resulting N-and O-containing receptors could be perspective as optical chemosensors for small chiral organic molecules.
Experimental
NMR spectra were registered using Bruker Avance 400 spectrometer in CDCl3 at 298 K. MALDI-TOF spectra were obtained with Bruker Autoflex II spectrometer using 1,8,9-trihydroxyan-thracene as matrix and PEGs as internal standards. Dioxa-, tri-oxa- and tetraoxadiamines 1a-e, (S)-BINAM, 1,3-dibromobenzene, 1-(bromomethyl)-3-bromobenzene, phosphine ligands BINAP, DavePhos and Xantphos, potassium carbonate, sodium tert-butox-ide, were purchased from Aldrich and used without further purification, Pd(dba)2 was synthesized according to the method described,[15] 2,7-dibromonaphthalene was obtained via known procedure.[16] Dioxane was distilled over NaOH followed by the distillation over sodium under argon, acetonitrile was distilled over CaH^ dichloro-methane and methanol were used freshly distilled. Compound 2 was synthesized according to a procedure described.[17]
7,14,15,17,18,21,22,28-Octahydro-13H,20H-8,12:27,23-dimethenodinaphtho[1,2-p:2',1'-n][1,4,7,13,18,24]dioxatet-raazacyclohexacosine (3a). A two-neck flask equipped with a magnetic stirrer and reflux condenser, flushed with dry argon, was charged with compound 2 (0.1 mmol, 46 mg), Pd(dba)2 (8 mol%, 4.5 mg), BINAP (9 mol%, 5.5 mg), absolute dioxane (5 ml), (S)-BINAM (0.1 mmol, 28.5 mg) was then added followed by sodium tert-butoxide (0.3 mmol, 29 mg). The reaction mixture was refluxed for 24 h, after cooling it down to ambient temperature the solvent was filtered, the precipitate was washed with CH2Cl2 (5 ml), combined organic fractions were evaporated in vacuo, and the residue was chromatographed on silica gel using a sequence of eluents: CH2Cl2, CH2Cl2/MeOH (200:1 - 3:1). The target compound 3a was obtained with the eluent CH2Cl2/MeOH (100:1) as a brown solid. Yield 20 mg (34 %). In the case when DavePhos (9 mol%, mg) was used instead of BINAP, the yield was 43 %. (MALDI-TOf) found: 581.2876. C38H37N4O2 requires 581.2917 [M+H]+. 1H NMR 8H ppm: 3.12 - 3.25 (4H, m), 3.61 (4H, s), 3.64 - 3.70 (4H, m), 5.51 (2H, s), 6.08 (2H, s), 6.19 (2H, dd, 3J=8.0 Hz, 4J=1.5 Hz), 6.35 (2H, dd, 3J=7.8 Hz, 4J=1.4 Hz), 6.97 (2H, t, 3J=8.0 Hz), 7.10 (2H, d, 3J=8.5 Hz), 7.20 - 7.24 (2H, m), 7.29 - 7.33 (2H, m), 7.68 (2H, d, 3J=9.0 Hz), 7.84 (2H, d, 3J=8.1 Hz), 7.86 (2H, d, 3J=9.0 Hz), two NH protons were not assigned. 13C NMR 8c ppm: 43.8 (2C), 69.1 (2C), 70.0 (2C), 104.3 (2C), 106.1 (2C), 109.2 (2C), 117.9 (2C), 119.4 (2C), 123.5 (2C), 124.9 (2C), 126.8 (2C), 128.1 (2C), 129.2 (2C), 129.6 (2C), 130.0 (2C), 134.4 (2C), 140.0 (2C), 144.1 (2C), 149.1 (2C).
N2,N2-Bis(3-bromophenyl)-(S)-1,1'-binaphthyl-2,2'-diamine (4). A two-neck flask equipped with a magnetic stirrer and reflux condenser, flushed with dry argon, was charged with 1,3-dibromo-
benzene (0.22 mmol, 52 mg), Pd(dba)2 (2 mol%, 1.2 mg), Xantphos (2.5 mol%, 1.2 mg), absolute dioxane (1 ml), (S)-BINAM (0.1 mmol, 28.5 mg) was then added followed by sodium tert-bu-toxide (0.3 mmol, 29 mg). The reaction mixture was refluxed for 8 h, after cooling it down to ambient temperature the solvent was filtered, the precipitate was washed with CH2Cl2 (5 ml), combined organic fractions were evaporated in vacuo, and the residue was chromatographed on silica gel using a sequence of eluents: hex-anes/CH2Cl2 (10:1 - 1:2). The target compound 4 was obtained with the eluent hexanes/CH2Cl2 (10:1) as a light-beige solid. Yield 47 mg (68 %). (MALDI-TOF) found: 593.0251. C32H23Br2N2 requires 593.0228 [M+H]+. 1H NMR 8H ppm: 5.46 (2H, br.s), (5.72 - 6.77 (2H, m), 6.94 - 6.98 (6H, m), 7.12 (2H, d, 3J=8.3 Hz), 7.23 - 7.27 (2H, m), 7.34 - 7.38 (2H, m), 7.65 (2H, d, 3J=8.8 Hz), 7.87 (2H, d, 3J=8.0 Hz), 7.92 (2H, d, 3J=8.8 Hz). 13C NMR 8c ppm: 117.0 (2C),
118.3 (2C), 118.9 (2C), 121.0 (2C), 123.0 (2C),c124.2 (2C), 124.4 (2C), 124.6 (2C), 127.3 (2C), 128.3 (2C), 129.7 (2C), 130.0 (2C),
130.4 (2C), 133.8 (2C), 139.0 (2C), 144.3 (2C).
Typical procedure for the synthesis of macrocycles 3a-e. A two-neck flask equipped with a magnetic stirrer and reflux condenser is flushed with dry argon, charged with compound 4, Pd(dba)2, DavePhos, absolute dioxane, corresponding oxadiamine is then added followed by sodium tert-butoxide. The reaction mixture is refluxed for 24 h, after cooling it down to ambient temperature the solvent is filtered, the precipitate is washed with CH2Cl2 (5 ml), combined organic fractions are evaporated in vacuo, and the residue is chromatographed on silica gel using a sequence of eluents: CH2Cl2, CH2Cl2/MeOH (200:1 - 3:1).
7,13,14,15,16,18,19,20,21,23,24,25,26,32-Tetradecahydro-8,12:31,27-dimethenodinaphtho[1,2-n:2',1'-l][1,26,5,11,16,22] dioxatetraazacyclotriacontine (3b). Obtained from compound 4 (0.17 mmol, 100 mg), dioxadiamine 2b (0.17 mmol, 34 mg), in the presence of Pd(dba)2 (8 mol%, 8 mg), DavePhos (8 mol%, 6 mg), and sodium tert-butoxide (0.51 mmol, 48 mg) in 5 ml of dioxane. Eluent: CH2Cl2/MeOH (50:1). Yield 27 mg (25 %). (MALDI-TOF) found: 637.3590. C42H45N4O2 requires 637.3543 [M+H]+. 1H NMR 8H ppm: 1.63-1.67 (4H, m), 1.80 (4H, quintet, 3J=5.9 Hz), 3.07 (4H, q, 3J=5.7 Hz), 3.42 - 3.46 (4H, m), 3.50 (4H, t, 3J=5.6 Hz), 3.94 (2H, br.s), 5.51 (2H, s), 6.03 (2H, t, 4J=2.0 Hz), 6.20 (2H, dd, 3J=8.1 Hz, 4J=2.0 Hz), 6.39 (2H, dd, 3J=7.8 Hz, 4J=2.0 Hz), 6.98 (2H, t, 3J=8.0 Hz), 7.12 (2H, d, 3J=8.3 Hz), 7.20 - 7.24 (2H, m), 7.28 - 7.32 (2H, m), 7.69 (2H, d, 3J=9.0 Hz), 7.83 (2H, d, 3J=8.2 Hz), 7.86 (2H, d, 3J=9.0 Hz). 13C NMR 8c ppm: 26.5 (2C), 29.3 (2C), 42.2 (2C), 69.3 (2C), 70.8 (2C), 104.2 (2C), 107.2 (2C), 108.8 (2C), 116.8 (2C), 118.9 (2C), 123.3 (2C), 124.7 (2C), 126.8 (2C), 128.1 (2C), 129.1 (2C), 129.4 (2C), 129.6 (2C), 134.1 (2C), 140.6 (2C), 143.9 (2C), 149.8 (2C).
7,14,15,17,18,20,21,24,25,31-Decahydro-13H,23H-8,12:30,26-dimethenodinaphtho[1,2-s:2',1'-q][1,4,7,10,16,21,27] trioxatetraazacyclononacosine (3c). Obtained from compound 4 (0.2 mmol, 181 mg), trioxadiamine 2c (0.2 mmol, 38 mg), in the presence of Pd(dba)2 (16 mol%, 18 mg), DavePhos (18 mol%, 14 mg), and sodium tert-butoxide (0.6 mmol, 58 mg) in 5 ml of dioxane. Eluent: CH2Cl2/MeOH (100:1). Yield 27 mg (22 %). (MALDI-TOF) found: 625.3258. C40H41N4O3 requires 625.3179 [M+H]+. 1H NMR 8H ppm: 3.04 - 3.16 (4H, m), 3.64 (8H, s), 3.65 (4H, t, 3J=5.1 Hz), 5.47 (2H, s), 6.05 (2H, s), 6.23 (2H, d, 3J=7.7 Hz), 6.34 (2H, d, 3J=7.7 Hz), 6.93 (2H, t, 3J=8.0 Hz), 7.10 (2H, d, 3J=8.5 Hz), 7.20 -7.24 (2H, m), 7.29 - 7.33 (2H, m), 7.65 (2H, d, 3J=9.0 Hz), 7.84 (2H, d, 3Jobs=6.8 Hz), 7.86 (2H, d, 3Job=8.6 Hz), two NH protons were not assigned.
1,7,8,9,10,12,13,15,16,18,19,20,21,27-Tetradecahydro-2,6:26,22-dimethenodinaphtho[1,2-t:2',1'-r][1,4,7,11,17,22,28] trioxatetraazacyclohentriacontine (3d). Obtained from compound 4 (0.13 mmol, 77 mg), trioxadiamine 2d (0.13 mmol, 29 mg), in the presence of Pd(dba)2 (8 mol%, 6 mg), DavePhos (9 mol%, 4.5 mg), and sodium tert-butoxide (0.39 mmol, 38 mg) in 5 ml of dioxane. Eluent: CH2Cl2/MeOH (100:1). Yield 22 mg (25 %). (MALDI-TOF)
found: 653.3528. C42H45N4O3 requires 653.3492 [M+H]+. 1H NMR 8H ppm: 1.78 (4H, quintet, 3J=6.0 Hz), 3.06 (4H, t, 3J=6.3 Hz), 3.55 (4H, t, 3J=5.7 Hz), 3.57 - 3.60 (4H, m), 3.61 - 3.64 (4H, m), 3.70 (2H, br.s), 5.46 (2H, s), 5.98 (2H, s), 6.22 (2H, d, 3J=7.8 Hz), 6.33 (2H, d, 3J=7.8 Hz), 6.94 (2H, t, 3J=7.8 Hz), 7.12 (2H, d, 3J=8.5 Hz), 7.21- 7.25 (2H, m), 7.29 - 7.33 (2H, m), 7.67 (2H, d, 3J=9.0 Hz), 7.84 (2H, d, 3Jobs=6.4 Hz), 7.86 (2H, d, 3Jobs=8.7 Hz). 13C NMR 8c ppm: 28.8 (2C°,42.0 (2C), 69.5 (2C), 70.2 s(2C), 70.6 (2C), 103.9' (2C), 107.5 (2C), 108.8 (2C), 117.5 (2C), 119.5 (2C), 123.4 (2C), 124.8 (2C), 126.8 (2C), 128.1 (2C), 129.1 (2C), 129.5 (2C), 129.6 (2C), 134.2 (2C), 140.4 (2C), 144.2 (2C), 149.2 (2C).
1,8,9,11,12,14,15,17,18,21,22,28-Dodecahydro-7H,20H-2,6:27,23-dimethenodinaphtho[1,2-v :2',1'-t] [1,4,7,10,13,19,24,30]tetraoxatetraazacyclodotriacontine (3e). Obtained from compound 4 (0.1 mmol, 59 mg), tetraoxadiamine 2e (0.1 mmol, 24 mg), in the presence of Pd(dba)2 (8 mol%, 4.5 mg), DavePhos (9 mol%, 3 mg), and sodium tert-butoxide (0.3 mmol, 28.5 mg) in 5 ml of dioxane. Eluent: CH2Cl2/MeOH (100:1). Yield 18 mg (27 %). (MALDI-TOF) found: (569.3493. C42H45N4O4 requires 669.3441 [M+H]+. 1H NMR 8H ppm: 3.05 - 3.12 (4H, m), 3.58 - 3.66 (16H, m), 5.49 (2H, s), 6.09 (2H, br.s), 6.28 (2H, d, 3J=8.1 Hz), 6.35 (2H, dd, 3J=7.6 Hz, 4J=1.0 Hz), 6.93 (2H, t, 3J=8.0 Hz), 7.10 (2H, d, 3J=8.7 Hz), 7.21 - 7.25 (2H, m), 7.29 - 7.33 (2H, m), 7.65 (2H, d, 3J=9.0 Hz), 7.84 (2H, 3Jobs=7.2 Hz), 7.86 (2H, 3Jobs=8.7 Hz), two NH protons were not assigned. 13C NMR 8c ppm: 44.0 (2C), 69.2 (2C), 70.3 (2C), 70.6 (2C), 70.7 (2C), 104i (2C),
108.1 (2C), 109.5 (2C), 117.3 (2C), 119.2 (2C), 123.4 (2C), 124.8 (2C), 126.8 (2C), 128.1 (2C), 129.1 (2C), 129.5 (2C), 129.8 (2C),
134.2 (2C), 140.3 (2C), 144.1 (2C), 148.8 (2C).
N2,N2-Bis(7-bromonaphthalen-2-yl)-(S)-1,1'-binaphthyl-2,2'-
diamine (5). A two-neck flask equipped with a magnetic stirrer and reflux condenser, flushed with dry argon, was charged with 2,7-di-bromonaphthalene (1.4 mmol, 400 mg), Pd(dba)2 (4 mol%, 12 mg), Xantphos (4.5 mol%, 13 mg), absolute dioxane (5 ml), (S)-BINAM (0.5 mmol, 142 mg) was then added followed by sodium tert-butox-ide (2 mmol, 192 mg). The reaction mixture was refluxed for 8 h, after cooling it down to ambient temperature the solvent was filtered, the precipitate was washed with CH2Cl2 (5 ml), combined organic fractions were evaporated in vacuo, and the residue was chroma-tographed on silica gel using a sequence of eluents: hexane/CH2Cl2 (10:1 - 1:2). The target compound 5 was obtained with the eluent hexanes/CH2Cl2 (4:1) as a beige solid. Yield 180 mg (52 %). (MAL-DI-TOF) found: 693.0511. C40H27Br2N2 requires 693.0541 [M+H]+. 1H NMR 8H ppm: 5.65 (2H, br.s), 6.81 (2H, d, 3J=8.8 Hz), 6.91 (2H, s), 7.19 - 7.44 (14H, m), 7.76 (2H, d, 3J=8.7 Hz), 7.93 - 7.98 (4H, m). 13C NMR 8c ppm: 110.4 (2C), 119.2 (2C), 119.9 (2C), 120.0 (2C), 120.4 (2C),c124.3 (2C), 124.7 (2C), 126.5 (2C), 127.2 (2C), 127.3 (2C), 128.0 (2C), 128.3 (2C), 128.9 (4C), 129.5 (2C), 130.1 (2C), 134.0 (2C), 135.2 (2C), 139.0 (2C), 141.7 (2C).
Typical procedure for the synthesis of macrocycles 6a,b,d,e. A two-neck flask equipped with a magnetic stirrer and reflux condenser is flushed with dry argon, charged with compound 5, Pd(dba), DavePhos, absolute dioxane, corresponding oxadiamine is then added followed by sodium tert-butoxide. The reaction mixture is refluxed for 24 h, after cooling it down to ambient temperature the solvent is filtered, the precipitate is washed with CH2Cl2 (5 ml), combined organic fractions are evaporated in vacuo, and the residue is chromatographed on silica gel using a sequence of eluents: CH2Cl2, CH2Cl2/MeOH (200:1 - 3:1).
Macrocycle 6a. Obtained from compound 5 (0.17 mmol, 117 mg), dioxadiamine 2a (0.17 mmol, 25 mg), in the presence of Pd(dba)2 (8 mol%, 8 mg), DavePhos (9 mol%, 6 mg), and sodium tert-butoxide (0.51 mmol, 49 mg) in 8 ml dioxane. Eluent: CH2Cl2/MeOH (200:1). Yield 40 mg (34 %). (MALDI-TOF) found: 681.3204. C46H41N4O2 requires 681.3230 [M+H]+. 1H NMR 8H ppm: 3.26 - 3.33 (4H, m), 3.69 (4H, s), 3.78 (4H, t, 3J=4.7 Hz), 3.98 (2H, br.s), 5.64 (2H, s), 6.30 (2H, s), 6.66 (2H, s), 6.68-6.76 (4H, m), 7.18 (2H, d, 3J=8.5 Hz), 7.25 - 7.30 (4H, m), 7.33 (2H,
d, 3J=8.5 Hz), 7.38 (2H, t, 3J=7.4 Hz), 7.74 (2H, d, 9.0 Hz), 7.90 (2H, d, 3J=8.1 Hz), 7.94 (2H, d, 3J=9.0 Hz), two NH protons were not assigned. 13C NMR 8c ppm: 53.4 (2C), 60.1 br. (2C), 69.4 (2C), 109.9 br. (2C), 114.7 (2C), 115.7 (2C), 121.1 br. (4C), 124.1 (2C), 125.1 (2C), 126.9 (2C), 128.2 (2C), 128.6 (2C), 128.7 (2C), 129.3 (2C), 130.1 (2C), 134.3 (2C), 135.4 br. (2C), 139.3 br. (2C), 142.1 (2C), six quaternary carbon atoms were not assigned due to line broadening.
Macrocycle 6b. Obtained from compound 5 (0.16 mmol, 110 mg), dioxadiamine 2b (0.16 mmol, 33 mg), in the presence of Pd(dba)2 (8 mol%, 7.5 mg), DavePhos (9 mol%, 6 mg), and sodium tert-butoxide (0.48 mmol, 46 mg) in 5 ml of dioxane. Eluent: CH2Cl2/MeOH (100:1). Yield 37 mg (31 %). (MALDI-TOF) found: 737.3937. C50H49N4O2 requires 737.3856 [M+H]+. 1H NMR 8H ppm: 1.70 - 1.74 (4H, m), 1.90 (4H, quintet, 3J=6.0 Hz), 3.13 - 3.26 (4H, m), 3.48 - 3.52 (4H, m), 3.58 (4H, t, 3J=5.5 Hz), 5.71 (2H, s), 6.31 (2H, br.s), 6.70 (2H, dd, 3J=8.3 Hz, 4J=1.5 Hz), 6.78 (2H, d, 4J=2.3 Hz), 6.83 (2H, dd, 3J=8.3 Hz, 4J=2.3 Hz), 7.17 (2H, d, 3J=8.0 Hz), 7.23 -7.27 (2H, m), 7.32 - 7.36 (2H, m), 7.43 (4H, d, 3J=8.7 Hz), 7.72 (2H, d, 3J=9.0 Hz), 7.87 (2H, d, 3J=8.0 Hz), 7.91 (2H, d, 3J=8.8 Hz), two NH protons were not assigned. 13C NMR 8c ppm: 26.5 (2C), 29.1 (2C), 42.8 br. (2C), 69.3 (2C), 70.8 (2C),
112.5 (2C), 116.2 (2C), 117.0 (2C), 117.9 (2C), 119.7 (2C), 123.6 (2C), 124.9 (2C), 126.9 (2C), 128.2 (2C), 128.4 (2C), 128.6 (2C), 129.3 (2C), 129.7 (4C), 134.2 (2C), 136.2 (2C), 140.3 (2C), 141.3 (2C), four quaternary carbon atoms were not assigned due to line broadening.
Macrocycle 6d. Obtained from compound 5 (0.26 mmol, 180 mg), trioxadiamine 2d (0.26 mmol, 57 mg), in the presence of Pd(dba)2 (8 mol%, 12 mg), DavePhos (9 mol%, 9 mg), and sodium ieri-butoxide (0.78 mmol, 75 mg) in 8 ml of dioxane. Eluent: CH2Cl2/MeOH (100:1). Yield 29 mg (15 %). (MALDI-TOF) found: 753.3846. C50H49N4O3 requires 753.3805 [M+H]+. 1H NMR 8H ppm: 1.81 - 1.95 (4H, m), 3.12 - 3.25 (4H, m), 3.62 - 3.72 (12H, m), 5.68 (2H, s), 6.15 (2H, s), 6.68 (2H, s), 6.71 (2H, d, 3J=9.0 Hz), 6.77 (2H, dd, 3J=8.6 Hz, 4J=1.9 Hz), 7.18 (2H, d, 3J=8.3 Hz), 7.24 - 7.28 (2H, m), 7.32 - 7.36 (2H, m), 7.38 (2H, d, 3J=8.7 Hz), 7.39 (2H, d, 3J=8.9 Hz), 7.71 (2H, d, 3J=8.8 Hz), 7.89 (2H, d, 3J=8.1 Hz), 7.91 (2H, d, 3J=9.1 Hz), two NH protons were not assigned. 13C NMR 8c ppm: 28.3 (2C), 43.2 br. (2C), 69.7 (2C), 70.2 (2C), 70.6 (2C),
115.6 (2C), 116.3 (2C), 116.8 (2C), 120.1 (2C), 123.8 (2C), 125.0 (2C), 126.9 (2C), 128.2 (2C), 128.4 (2C), 128.6 (2C), 129.3 (2C),
129.7 (2C), 129.9 (2C), 134.3 (2C), 136.0 (2C), 140.0 (2C), 141.7 (2C), six quaternary carbon atoms were not assigned due to line broadening.
Macrocycle 6e. Obtained from compound 5 (0.1 mmol, 69 mg), tetraoxadiamine 2e (0.1 mmol, 24 mg), in the presence of Pd(dba)2 (16 mol%, 9 mg), DavePhos (18 mol%, 7 mg), and sodium tert-butoxide (0.3 mmol, 29 mg) in 5 ml of dioxane. Eluent: CH2Cl2/MeOH (100:1). Yield 5 mg (7 %). (MALDI-TOF) found: 769.3815. C50H49N4O4 requires 769.3754 [M+H]+. 1H NMR 8H ppm: 3.18 (4H, br.s), 3.65 - 3.75 (16H, m), 5.65 (2H, s), 6.22 (2H, br.s), 6.71 (2H, s), 6.73 - 6.79 (4H, m), 7.17 (2H, d, 3J=8.0 Hz), 7.28 (2H, d, 3J=8.1 Hz), 7.31- 7.40 (6H, m), 7.71 (2H, d, 3J=9.0 Hz), 7.89 (2H, d, 3J=8.6 Hz), 7.93 (2H, d, 3J=9.2 Hz), two NH protons were not assigned.
N2,N2-Bis(3-bromobenzyl)-(S)-1,1'-binaphthyl-2,2'-diamine (7). A two-neck flask equipped with a magnetic stirrer and reflux condenser, flushed with dry argon, was charged with (S)-BINAM (1 mmol, 284 mg), 1-(bromomethyl)-3-bromobenzene (2 mmol, 496 mg), acetonitrile (10 ml) and potassium carbonate (4 mmol, 552 mg). The reaction mixture was stirred at reflux for 24 h, after cooling it down to ambient temperature the solvent was filtered, the precipitate was washed with CH2Cl2 (5 ml), combined organic fractions were evaporated in vacuo, and the residue was chromato-graphed on silica gel using a sequence of eluents: hexanes/CH2Cl2 (4:1- 1:2), CH2Cl2. The target compound 7 was obtained with the eluent hexanes/CH2Cl2 (1:1) as a yellow viscous oil. Yield 199 mg
(32 %). (MALDI-TOF) found: 621.0505. C34H27Br2N2 requires 621.0541 [M+H]+. Щ NMR SH ppm: 4.35 (2H, br.s), 4.40 (4H, s), 7.08 - 7.16 (8H, m), 7.24 - 7.30 (4H, m), 7.33 (2H, d, 3J=7.7 Hz), 7.40 (2H, s), 7.78 - 7.81 (2H, m), 7.84 (2H, d, 3J=9.0 Hz). 13C NMR Sc ppm: 46.7 (2C), 112.0 (2C), 113.9 (2C), 122.3 (2C), 122.7 (2C), 123.7 (2C), 125.3 (2C), 127.1 (2C), 127.8 (2C), 128.2 (2C), 129.6 (2C), 129.8 (2C), 130.0 (2C), 133.7 (2C), 142.3 (2C), 143.5 (2C).
N2,N2,N2-Tris(3-bromobenzyl)-(S)-1,1'-binaphthyl-2,2'-diamine (9). Obtained as the second product in the synthesis of compound 7. Eluent: hexanes/CH2Cl2 (2:1). Yield 117 mg (15 %). (MALDI-TOF) found: 789.0180. C41H32Br3N2 requires 789.0116 [M+H]+. 1H NMR SH ppm: 3.98 (2H, d, 2J=14.7 Hz), 4.00 (1H, br.s), 4.03 (2H, d, 2J=14.7 Hz), 4.25 (1H, d, 2J=15.8 Hz), 4.42 (1H, d, 2J=15.8 Hz), 6.77 (2H, d, 3J=7.6 Hz), 6.95 - 7.02 (7H, m), 7.12 (1H, d, 3J=8.8 Hz), 7.18 - 7.28 (5H, m), 7.30 - 7.36 (2H, m), 7.43 (1H, ddd, 3J=7.8 Hz, 3J=6.1 Hz, 4J=1.9 Hz), 7.48 (1H, d, 3J=8.9 Hz), 7.80 - 7.85 (2H, m), 7.92 (1H, d, 3J=8.1 Hz), 7.96 (1H, d, 3J=8.8 Hz). 13C NMR Sc ppm: 47.1 (1C), 56.2 (2C), 113.7 (1C), 115.5 (1C), 122.1 (1C), 122.2 (2C), 122.6 (1C), 124.1 (1C), 124.9 (1C), 125.2 (1C), 125.3 (1C), 125.8 (1C), 126.7 (1C), 127.0 (1C), 127.1 (2C), 127.7 (1C), 128.1 (1C), 128.3 (1C), 129.1 (1C), 129.4 (3C), 129.7 (1C), 129.9 br. (4C), 130.8 (1C), 131.5 (2C), 133.6 (2C), 140.5 (3C), 142.2 (1C), 142.5 (1C), 149.0 (1C).
N2,N2-Bis(3-bromobenzyl)-(S)-1,1'-binaphthyl-2,2'-di-amine (10). Obtained as the third product in the synthesis of compound 7. Eluent: hexanes/CH2Cl2 (1:2).Yield 31 mg (5 %) (in the mixture with compound 7). (MALDI-TOF) found: 621.0488. C34H27Br2N2 requires 621.0541 [M+H]+. 1H NMR SH ppm: 3.998 (2H, d, 2J=14.8 Hz), 4.03 (2H, d, 2J=14.8 Hz), 6.81 (2H, d, 3J=7.7 Hz), 7.00 (2H, t, 3J=7.8 Hz), 7.03 (1H, d, 3J=7.8 Hz), 7.06 (2H, s), 7.10 - 7.35 (10H, m), 7.24 (1H, ddd, 3J=8.3 Hz, 3J=6.8 Hz, 4J=1.4 Hz), 7.42 -7.46 (1H, m), 7.53 (1H, d, 3J=8.8 Hz), 7.83 - 7.89 (2H, m), 7.93 (1H, d, 3J=8.2 Hz), 7.98 (1H, d, 3J=8.8 Hz), two NH protons were not assigned.
N2-(3-Bromobenzyl)-(S)-1,1'-binaphthyl-2,2'-diamine (11). Obtained as the fourth product in the synthesis of compound 7. Eluent: CH2Cl2.Yield 100 mg (22 %). (MALDI-TOF) found: 453.0937. C27H22BrN2 requires 453.0966 [M+H]+. 1H NMR SH ppm: 3.83 (3H, br.s), 4.36 (2H, s), 7.07 - 7.15 (5H, m), 7.17 (1H, d, 3J=8.8 Hz), 7.19 - 7.23 (2H, m), 7.26 - 7.30 (2H, m), 7.32 (1H, d, 3J=7.7 Hz), 7.40 (1H, s), 7.77 - 7.85 (4H, m). 13C NMR Sc ppm: 46.8, 112.0, 112.6, 113.9, 118.3, 122.1, 122.5, 122.7, 123.7, 123.9, 125.4, 126.8, 127.0, 127.7, 128.1, 128.2, 128.5, 129.6, 129.7 (2C), 130.0 (2C), 133.5, 133.9, 142.4, 142.9, 143.3.
Typical procedure for the synthesis of macrocycles 12a,b,d. A two-neck flask equipped with a magnetic stirrer and reflux condenser is flushed with dry argon, charged with compound 7, Pd(dba)2, BINAP, absolute dioxane, corresponding oxadiamine is then added followed by sodium tert-butoxide. The reaction mixture is refluxed for 24 h, after cooling it down to ambient temperature the solvent is filtered, the precipitate is washed with CH2Cl2 (5 ml), combined organic fractions are evaporated in vacuo, and the residue is chro-matographed on silica gel using a sequence of eluents: CH2Cl2, CH2Cl2/MeOH (200:1 - 3:1).
7,8,15,16,18,19,22,23,29,30-Decahydro-14H,21H-9,13:28,24-dimethenodinaphtho[1,2-q:2 ', 1 '-o][1,4,7,14,19,26] dioxatetraazacyclooctacosine (12a). Obtained from compound 7 (0.13 mmol, 82 mg), dioxadiamine 2a (0.13 mmol, 19 mg), in the presence of Pd(dba)2 (8 mol%, 6 mg), BINAP (9 mol%, 8 mg), and sodium tert-butoxide (0.39 mmol, 40 mg) in 4 ml of dioxane. Eluent: CH2Cl2/MeOH (100:1). Yield 32 mg (41 %). (MALDI-TOF) found: 609.3180. C40H41N4O2 requires 609.3230 [M+H]+. 1H NMR SH ppm: 3.11 (4H, t, 3J=4.9 Hz), 3.53 (4H, t, 3J=4.9 Hz), 3.54 (4H, s), 4.22 (2H, d, 2J=15.3 Hz), 4.34 (2H, d, 2J=15.3 Hz), 4.68 (2H, s), 6.47 (2H, d, 3J=8.5 Hz), 6.49 (2H, s), 6.56 (2H, d, 3J=7.2 Hz), 6.99 - 7.05 (4H, m), 7.14 - 7.22 (4H, m), 7.24 (2H, d, 3J=7.5 Hz), 7.73-7.76 (2H, m), 7.82 (2H, d, 3J=9.0 Hz), two NH protons were not assigned. 13C NMR S ppm: 43.7 (2C), 48.3 (2C), 69.3 (2C),
70.2 (2C), 111.6 (2C), 112.1 (4C), 114.6 (2C), 116.5 (2C), 121.9 (2C), 123.9 (2C), 126.7 (2C), 127.8 (2C), 128.1 (2C), 129.3 (2C), 129.6 (2C), 133.8 (2C), 141.0 (2C), 144.7 (2C), 148.1 (2C).
1.2.8.9.10.11.13.14.15.16.18.19.20.21.27.28-Hexa-decahydro-3,7:26,22-dimethenodinaphtho[1,2-o:2',1'-m] [1,28,5,12,17,24]dioxatetraazacyclodotriacontine (12b). Obtained from compound 7 (0.13 mmol, 82 mg), dioxadiamine 2b (0.13 mmol, 26 mg), in the presence of Pd(dba)2 (8 mol%, 6 mg), BINAP (9 mol%, 8 mg), and sodium tert-butoxide (0.39 mmol, 40 mg) in 4 ml of dioxane. Eluent: CH2Cl2/MeOH (200:1). Yield 38 mg (44 %). (MALDI-TOF) found: 665.3817. C44H49N4O2 requires 665.3856 [M+H]+. 1H NMR SH ppm: 1.62 - 1.66 (4H, m), 1.77 (4H, quintet, 3J=5.7 Hz), 3.09 (4H, t, 3J=6.0 Hz), 3.38 - 3.42 (4H, m), 3.46 (4H, t, 3J=5.4 Hz), 4.19 -4.38 (6H, m), 6.40 (2H, d, 3J=7.5 Hz), 6.46 (2H, s), 6.50 (2H, d, 3J=8.0 Hz), 6.98 (2H, t, 3J=7.7 Hz), 7.01 - 7.05 (2H, m), 7.15 - 7.21 (6H, m), 7.73 -7.77 (2H, m), 7.80 (2H, d, 3J=8.9 Hz), two NH protons were not assigned. 13C NMR Sc ppm: 26.7 (2C), 29.2 (2C), 42.1 (2C), 47.7 (2C), 69.5 (2C), 70.8 (2C), 110.8 (2C), 111.1 (2C), 111.9 (2C), 114.3 (2C), 115.4 (2C), 121.8 (2C), 123.9 (2C), 126.6 (2C), 128.0 (2C), 129.3 (2C),
129.5 (2C), 133.9 (2C), 140.9 (2C), 144.4 (2C), 148.9 (2C).
1.2.8.9.10.11.13.14.16.17.19.20.21.22.28.29-Hexadecahydro-3,7:27,23-dimethenodinaphtho[1,2-u:2',1'-s][1,4,7,11,18,23,30] trioxatetraazacyclotritriacontine (12d). Obtained from compound 7 (0.13 mmol, 82 mg), trioxadiamine 2d (0.13 mmol, 29 mg), in the presence of Pd(dba)2 (8 mol%, 6 mg), BINAP (9 mol%, 8 mg), and sodium tert-butoxide (0.39 mmol, 40 mg) in 4 ml of dioxane. Eluent: CH2Cl2/MeOH (100:1). Yield 39 mg (45 %). (MALDI-TOF) found: 681.3759. C44H49N4O3 requires 681.3805 [M+H]+. 1H NMR SH ppm: 1.74 (4H, quintet, 3J=6.0 Hz), 3.08 (4H, t, 3J=6.3 Hz), 3.52 (4H, t, 3J=5.8 Hz), 3.54 - 3.57 (4H, m), 3.60 - 3.63 (4H, m), 4.25 (2H, d, 2J=15.7 Hz), 4.30 (2H, br.s), 4.44 (2H, d, 2J=15.7 Hz), 6.48 (2H, d, 3J=7.7 Hz), 6.52 (2H, s), 6.56 (2H, d, 3J=7.6 Hz), 6.99 - 7.04 (4H, m), 7.14 - 7.20 (6H, m), 7.73 - 7.77 (2H, m), 7.81 (2H, d, 3J=9.0 Hz), two NH protons were not assigned. 13C NMR S ppm: 28.6 (2C), 42.3 (2C), 47.7 (2C), 69.8 (2C), 70.1 (2C), 70.6c (2C),
111.6 (4C), 111.8 (2C), 114.2 (2C), 116.0 (2C), 121.8 (2C), 123.9 (2C), 126.6 (2C), 127.7 (2C), 128.1 (2C), 129.3 (2C), 129.6 (2C), 133.9 (2C), 141.0 (2C), 144.4 (2C), 148.2 (2C).
N2,N2 -Bis(3,5-dibromobenzyl)-(S)-1,1'-binaphthyl-2,2 '-diamine (13). A two-neck flask equipped with a magnetic stirrer and reflux condenser, flushed with dry argon, was charged with (S)-BI-NAM (2.4 mmol, 674mg), 1,3-dibromo-5-(bromomethyl)benzene (4.8 mmol, 1551 mg), acetonitrile (24 ml) and potassium carbonate (9.6 mmol, 1325 mg). The reaction mixture was stirred at reflux for 24 h, after cooling it down to ambient temperature the solvent was filtered, the precipitate was washed with CH2Cl2 (10 ml), combined organic fractions were evaporated in vacuo, and the residue was chromatographed on silica gel using a sequence of eluents: hex-anes/CH2Cl2 (10:1 - 1:1). The target compound 13 was obtained with the eluent hexanes/CH2Cl2 (2:1) as a yellow viscous oil. Yield 1424 mg (76 %). (MALDI-TOF) found: 776.8662. C34H25Br4N2 requires 776.8751 [M+H]+. 1H NMR SH ppm: 4.41 (4H, s), 4.45 (2H, br.s), 7.11 (2H, d, 3J=9.0 Hz), 7.21 (2H, d, 3J=8.3 Hz), 7.23 (2H, ddd, 3J=8.1 Hz, 3J=7.0 Hz, 4J=1.3 Hz), 7.37 (4H, d, 4J=1.8 Hz), 7.38 (2H, ddd, 3J=8.3 Hz, 3J=7.0 Hz, 4J=1.4 Hz), 7.55 (2H, t, 4J=1.8 Hz), 7.86 (2H, d, 3J=7.8 Hz), 7.90 (2H, 3J=9.0 Hz). 13C NMR Sc ppm: 46.0 (2C), 111.9 (2C), 113.5 (2C), 122.5 (2C), 123.1 (4C),c 123.6 (2C), 127.4 (2C), 127.8 (2C), 128.3 (6C), 130.0 (2C), 132.5 (2C), 133.6 (2C), 142.9 (2C), 144.1 (2C).
N2,N2,N2-Tris(3,5-dibromobenzyl)-(S)-1,1'-binaphthyl-2,2'-diamine (14). Obtained as the second product in the synthesis of compound 13. Eluent: hexanes/CH2Cl2 (10:1). Yield 150 mg (9 %). (MALDI-TOF) found: 1022.71. C41H29Br6N2 requires 1022.74 [M+H]+. 1H NMR SH ppm: 3.95 (1H, br.s), 3.97 (4H, s), 4.22 (1H, dd, 2J=16.8 Hz, 3J=4.8 Hz), 4.43 (1H, dd, 2J=16.8 Hz, 3J=6.8 Hz), 6.81 (4H, d, 4J=1.5 Hz), 6.89 - 6.92 (1H, m), 7.06 (1H, d, 3J=9.0 Hz), 7.15 (2H, d, 4J=1.3 Hz), 7.19 - 7.27 (2H, m), 7.31 (1H, d, 3J=8.2 Hz),
7.37 (2H, t, 4J=1.5 Hz), 7.37-7.41 (1H, m), 7.43 (1H, t, 3J=1.3 Hz), 7.45 - 7.49 (1H, m), 7.53 (1H, d, 3J=9.0 Hz), 7.80 - 7.83 (1H, m), 7.86 (1H, d, 3J=9.1 Hz), 7.94 (1H, 3J=8.1 Hz), 8.02 (1H, 3J=8.8 Hz). 13C NMR8c ppm: 46.5 (1C), 57.5 (2C), 113.5, 115.4, 121.6, 122.5, 123.1, 123.7, 125.3, 125.5, 126.4, 127.1, 127.6, 127.8, 128.2, 128.4, 128.6, 129.7, 129.9, 130.1, 131.2, 132.5, 132.6, 133.5, 133.6, 141.9, 142.1, 143.9, 148.9 (integration of the aromatic carbons is ambiguous).
N2-(3,5-Dibromobenzyl)-1,1'-binaphthyl-2,2'-diamine (15). Obtained as the third product in the synthesis of compound 13. Elu-ent: hexanes/CH2Cl2 (2:1). Yield 200 mg (16 %). (MALDI-TOF) found: 531.0029. C27H21Br2N2 requires 531.0072 [M+H]+. 1H NMR 8H ppm: 3.73 (2H, br.s), 4.31 (2H, s), 4.32 (1H, br.s), 7.03 (1H, d, 3J=9.0 Hz), 7.11 - 7.16 (2H, m), 7.18 (1H, d, 3J=8.7 Hz), 7.20 - 7.25 (2H, m), 7.28 - 7.34 (2H, m), 7.35 (2H, d, 4J=1.5 Hz), 7.51 (1H, t, 4J=1.5 Hz), 7.78 - 7.87 (4H, m). 13C NMR 8c ppm: 46.1 (1C), 111.8 (1C), 112.7 (1C), 113.6 (1C), 118.3 (1C), 122.3 (1C), 122.6 (2C), 123.1 (1C), 123.7 (1C), 123.8 (1C), 126.9 (1C), 127.2 (1C), 127.8 (1C), 128.1 (1C), 128.2 (1C), 128.4 (3C), 129.7 (2C), 132.5 (1C), 133.4 (1C), 133.8 (1C), 142.8 (1C), 142.9 (1C), 144.2 (1C).
Macrocycle 16. A two-neck flask equipped with a magnetic stirrer and reflux condenser is flushed with dry argon, charged with compound 13 (0.25 mmol, 194 mg), Pd(dba)2 (16 mol%, 23 mg), BINAP (18 mol%, 28 mg), absolute dioxane (12 ml), trioxadiamine 2d (0.5 mmol, 110 mg) is then added followed by sodium tert-bu-toxide (0.75 mmol, 72 mg). The reaction mixture is refluxed for 24 h, after cooling it down to ambient temperature the solvent is filtered, the precipitate is washed with CH2Cl2 (5 ml), combined organic fractions are evaporated in vacuo, and the residue is chro-matographed on silica gel using a sequence of eluents: CH2Cl2, CH2Cl2/MeOH (200:1 - 50:1). The macrocycle 16 was obtained with CH2Cl2/MeOH (100:1) as a yellow viscous oil, yield 28 mg (13 %). (MALDI-TOF) found: 837.1954. C44H47Br2N4O3 requires 837.2015 [M+H]+. 1H NMR 8H ppm: 1.68 (4141, quintet, 3J=5.3 Hz), 2.97 - 3.02 (4H, m), 3.48 - 3.52 (4H, m), 3.54 - 3.57 (4H, m), 3.60 - 3.63 (4H, m), 4.19 (2H, dd, 2J=15.5 Hz, 3J=4.5 Hz), 4.27 (2H, dd, 3J=5.4 Hz, 3J=4.5 Hz), 4.34 (2H, dd, 2J=15.5 Hz, 3J=5.4 Hz), 6.35 (2H, s), 6.53 (2H, s), 6.64 (2H, s), 7.01 - 7.05 (2H, m), 7.14 (2H, d, 3J=9.1 Hz), 7.18 - 7.23 (4H, m), 7.76 - 7.80 (2H, m), 7.83 (2H, d, 3J=9.1 Hz). 13C NMR 8c ppm: 28.5 (2C), 41.7 (2C), 47.1 (2C), 69.7 (2C), 70.0 (2C), 70.5 (2C), 109.5 (2C), 111.9 (2C), 113.5 (2C), 114.0 (2C), 117.8 (2C), 122.1 (2C), 123.3 (2C), 123.8 (2C), 126.9 (2C), 127.8 (2C), 128.1 (2C), 129.8 (2C), 133.8 (2C), 142.8 (2C), 144.0 (2C), 150.1 (2C).
Results and Discussion
As BINAM molecule contains two identical primary amino groups, to furnish a macrocyclic structure with poly-
amine chain by means of Pd(0)-catalyzed amination, one needs to introduce the aromatic spacer between nitrogen atoms of BINAM and polyamine. At first we compared two approaches for introducing such spacer, the first one employing the reaction of BINAM with N,N'-bis(bromophenyl) substituted oxadiamine, the second one using the coupling of N,N'-bis(bromophenyl) substituted binaphthalene-2,2'-diamine with free oxadiamine. According to the first method, we synthesized N,N'-di(3-bromophenyl) substituted dioxa-diamine 2 starting from dioxadiamine 1a according to the known procedure,[17] and then introduced it in the macrocy-clization reaction with (S)-BINAM using two catalytic systems: Pd(dba)2/BINAP and Pd(dba)2/DavePhos (Scheme 1). The reactions were run in boiling dioxane with equimolar amounts of the reagents (c=0.02 M) in the presence of sodium tert-butoxide taken as a base.
The target macrocycle 3a was obtained by the column chromatography on silica gel and it was found that DavePhos provided slightly better results than BINAP (43 % compared to 34 %). Here and further all compounds were isolated by column chromatography and reported yields correspond to isolated products. Using the second method, at first N,A^'-di(3-bromophenyl) substituted BINAM 4 was synthesized in 68 % yield by reacting BINAM with 2.2 equiv. 1,3-dibromobenzene in the presence of Pd(dba)2/Xantphos catalytic system (Scheme 2). The necessity to use Xantphos instead of more universal BINAP ligand is explained by a high reactivity of the amino groups in BINAM that results in the formation of a considerable amount of linear oligomers caused by the diamination of 1,3-dibromobenzene. The second macrocyclization step with dioxadiamine 1a was run using Pd(dba)2/DavePhos catalytic system and gave the target macrocycle 3a in 53 % yield (Scheme 2) what is a good result for the catalytic macrocyclization reactions. The overall yield of the macrocycle according to the first method was 21 % while in the second method it attained 36 % thus we chose it for the synthesis of other oxadiazam-acrocycles. Moreover, the chromatographic isolation of the intermediate compound 4 is much easier than that of oxadiamine derivative 2.
The reactions of other oxadiamines 3b-d differing in the number of the oxygen atoms and chain length were conducted under stated conditions and produced similar results: the yields of the macrocyclization products ranged
Br v Br
„ „ .... 2.5 equiv. H2N O O NH2 _-_
1a Pd(dba)2/BINAP
fBuONa, dioxane
L1 =
Br'
NH O O HN 2,49%
Br Pd(dba)2/L1 or L2 /BuONa, dioxane
L1 = rac-BINAP L2 = DavePhos
HUH
3a, 34%(L1), 43%(L2)
Scheme 1.
''NH2
Br ^ Br 2.2 equiv.
nh2 Pd(dba)2/Xantphos fBuONa, Dioxane
H3C4 CH3
PPh2 PPh2 Xantphos
4, 68%
PdfdbaJ^DavePhos fBuONa, Dioxane
3 a-e
За, X = OCHjCHaO, 53%
3b, X = CH20(CH2)40CH2, 25%
3c, X = 0CH2CH20CH2CH20, 22%
3d, X = CH2OCH2CH2OCH2CH2OCH2 25%
Зе, X = 0(CH2CH20)3, 27%
Scheme 2.
from 22 to 27 %, thus only the diamine with the shortest chain provided two times higher yield, probably due to a better adjustment of its two amino groups to two bromine atoms in the compound 4.
A similar approach was used for the synthesis of the macrocycles possessing two 2,7-disubstituted naphthalene moieties. The reaction of BINAM with 2.5 equiv. of 2,7-di-bromonaphthalene afforded ^,^'-di(7-bromonaphth-2-yl) derivative 5 in 52 %% yield, and this compound was introduced in the series of catalytic macrocyclization reactions with the same oxadiamines 1a-e (Scheme 3). Again the best result was obtained with the shortest oxadiamine 1a (34 % yield of the corresponding macrocycle 6a), rather good yield was also provided by another oxadiamine 1b with a longer chain, (31 % yield of 6b). However, the results with other oxadiamines were less encouraging: trioxadiamine 1d gave 15 % yield of the macrocyclization poroduct 6d, tetraoxadi-amine 1e cyclized into the target product only in 7 % yield, while trioxadiamine 6c provided corresponding macrocycle 6c only in trace amounts in the reaction mixture. We may propose the same explanation for the observing effect of the chain length as in the case with macrocycles 3, but in the reaction of oxadiamines with dinaphthyl derivative 5 this dependence is more pronounced due to a longer distance between two bromine atoms participating in the intramolecular cyclization.
In our previous works dealing with the synthesis of macrocycles by Pd(0)-catalyzed intramolecular diamination of dihaloarenes we found out that in many cases the substitution of the second halogen atom proceeded with difficul-
ties.[18-21] On the other hand, catalytic macrocyclization of di(bromobenzyl) derivatives afforded enough high yields. [22-25] We attempted the synthesis of N,N'-di(3-bromobenzyl) substituted BINAM by the reaction with 2 equiv. of 3-bro-mobenzyl bromide in boiling MeCN in the presence of potassium carbonate and isolated the target compound 7 in 32 % yield (Scheme 4). This modest result is explained by the inevitable formation of the side products of tetra- and tribenzylation 8 and 9, the isomeric N,N-di(3-bromobenzyl) derivative 10 and monobenzylated BINAM 11. Compounds 9 and 11 were isolated in pure state (yields 15 and 22 %), isomer 10 was obtained and characterized in the mixture with the target compound 7.
Compound 7 was introduced in the macrocyclization reaction with oxadiamines 1a,b,d, in this case Pd(dba)2/ BINAP catalytic system was applied as it was observed earlier that BINAP is more helpful for the amination reactions of bromobenzyl derivatives. As it was expected, the macrocyclization reactions proceeded more successfully than in the previous cases, and all target macrocycles 12a,b,d were obtained in 41- 45 % yields (Scheme 4). It is supposed that two factors make the reaction in this case easier: the amination of bromobenzyl moiety proceeds smoother than that of aminobromophenyl moiety, and conformational factors are more favorable in the case of bromobenzyl amination.
At the last step of our investigation we synthesized N,N'-di(3,5-dibromobenzyl) substituted BINAM 13 via a similar reaction with 3,5-dibromobenzyl bromide (Scheme 5), in this process the yield of the target product attained 76 % while
,, Br v v Br
NH2 2.5 equiv.
.NH2 --
Pd(dba)2/Xantphos
fBuONa, Dioxane
5, 52%
H2N v 47 NH2 1a-e
Br Pd(dba)2/DavePhos fBuONa, Dioxane
6a, X = 0CH2CH20, 34%
6b, X= CH20(CH2)40CH2, 31%
6c, X = 0CH2CH20CH2CH20, traces
6d,X= CH20CH2CH20CH2CH20CH2 15%
бе, X = 0(СН2СН20)з, 7%
Scheme 3.
7, 32%
Br
8: R1 = R2 = R3 = 3-BrC6H4, traces 9: R1 = H, R2 = R3 = 3-BrC6H4, 15% 10: R1 = 3-BrC6H4, R2 = R3 = H, 5% (in mixture with 7) 11: R1 = R2 = R3= H, 22%
Br
1a,b,d
Pd(dba)2/BINAP fBuONa, dioxane
12a, X=0CH2CH20, 41%
12b, X = CH20(CH2)40CH2, 44%
12d, X = CH20CH2CH20CH2CH20CH2,45%
Scheme 4.
14: R1 = R2= 3,5-diBrC6H3, 9% 15: R1 = R2 = H, 16%
13
Br
r ^ 0 ~
k^,NH2 H2N 1d, 2 equiv.
Pd(dba)2/BINAP fBuONa, dioxane
Scheme 5.
tribenzylated and monobenzylated by-products 14 and 15 were isolated in 9 and 16 %, respectively. The compound 13 was introduced in the reaction with 2 equiv. of trioxadiamine 1d using Pd(dba)2/BINAP catalytic system in view of the synthesis of macrobicyclic compound, however, only macrocycle 16 was obtained in 13 % yield. The substitution of one bromine atom in each benzyl substituent took place and
no evidence of the diamination of the phenyl ring could be received from the 'H NMR spectrum of the reaction mixture. We tried another donor phosphine ligand, RuPhos which was thought to promote diamination, and in the reaction mixture weak signals of 3,5-diaminobenzyl group were observed in NMR spectrum, but no product could be isolated by chromatography in this case.
Macrocycles Containing Endocyclic Chiral BINAM Moieties Conclusions
To sum up, we developed the catalytic approach to a previously unknown class of N- and O-containing macrocycles comprising chiral BINAM fragment. The method consists of two subsequent Pd(0)-catalyzed amination reactions - the first step is the synthesis of corresponding N,N'-di(bromoaryl) substituted BINAM, the second is Pd(0)-mediated macrocyclization with linear oxadiamines. This approach was demonstrated to be enough general for the synthesis of macrocycles possessing various aryl spacers (phenyl, benzyl and naphthalene) and oxadiamine chains. The dependence of the compounds yields on the structure of starting compounds was established. The reaction of N,N'-di(3,5-dibromobenzyl) substituted BINAM with trioxadi-amine led to substitution of one bromine atom in each benzyl moiety and formation of a similar macrocyclic compound.
Acknowledgements. This work was financially supported by the RFBR grant 15-03-04698.
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Received 20.10.2016 Accepted 09.12.2016
